This proposal examines the functions of soluble helper factors in cytotoxic T lymphocyte (CTL) development. Our data suggest that a T cell factor and a macrophage (MO) factor, both of which are distinct from Interleukin 1 (IL 1), Interleukin 2 (IL 2) and interferon (IFN), assist CTL develolment. The functions of IL 1 and IL 2 are well documented; IL 1 induces a subset of T cells to produce IL 2 which stimulates the clonal expansion of antigen stimulated T cells. This proposal will focus on the functions of the less well defined T cell factor and MO factor and their relationship to IL 1, IL 2 and IFN. We will test the hypothesis that the T cell factor activates MO to produce a MO factor which provides a differentiative signal to antigen stimulated pre-CTLs that assists their development to antigen specific CTLs. We will examine whether these two factors synergize with, or are active in a pathway distinct from IL 1, IL 2 and IFN. The approach to this question will make use of current evidence suggesting that there are two subsets of both helper T cells and pre-CTLs, each of which is responsive to specific subsets of antigens. We will examine the antigens which stimulate production of these five factors as well as the subsets of T cells which produce, and the subsets of T cells which respond to specific factors. Such information should determine whether single or multiple pathways of CTL development exist. We will investigate the role of genetic restrictions in regulating the T cell-MO collaborations which are involved in factor production. The relationship of the T cell factor and MO factor to previously described lymphokins/monokins will be investigated. The T cell factor and MO factor will be tested for activities previously ascribed to other factors and conversely, other factors will be tested for the ability to assist CTL development. This will determine whether a single factor regulates several immune response. Knowledge of the regulatory role of soluble factors in immune responses may be important in tumor immunotherpy. In vitro, cytotoxic responses against some tumors require helper factors, and there is evidence that some tumors excape the immune system by not stimulating factor production. Regulation of factor production may be important in the management of patients with autoimmune diseases or those bearing allografts.